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Human Molecular Genetics Advance Access originally published online on April 13, 2005
Human Molecular Genetics 2005 14(11):1405-1415; doi:10.1093/hmg/ddi149
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

The Charcot–Marie–Tooth type 2A gene product, Mfn2, up-regulates fuel oxidation through expression of OXPHOS system

Sara Pich1, Daniel Bach1, Paz Briones2, Marc Liesa1, Marta Camps1, Xavier Testar1, Manuel Palacín1 and Antonio Zorzano1,*

1Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, and IRBB-PCB, Parc Científic de Barcelona, Barcelona, Spain and 2Institut de Bioquímica Clínica, Corporació Sanitària, Barcelona, Spain

* To whom correspondence should be addressed. Tel: +34 934037197; Fax: +34 934034717; Email: azorzano{at}pcb.ub.es

Received January 10, 2005; Revised March 11, 2005; Accepted March 29, 2005

Mitofusin-2 (Mfn2) is a mitochondrial membrane protein that participates in mitochondrial fusion in mammalian cells and mutations in the Mfn2 gene cause Charcot–Marie–Tooth neuropathy type 2A. Here, we show that Mfn2 loss-of-function inhibits pyruvate, glucose and fatty acid oxidation and reduces mitochondrial membrane potential, whereas Mfn2 gain-of-function increases glucose oxidation and mitochondrial membrane potential. As to the mechanisms involved, we have found that Mfn2 loss-of-function represses nuclear-encoded subunits of OXPHOS complexes I, II, III and V, whereas Mfn2 overexpression induced the subunits of complexes I, IV and V. Obesity-induced Mfn2 deficiency in rat skeletal muscle was also associated with a decrease in the subunits of complexes I, II, III and V. In addition, the effect of Mfn2 overexpression on mitochondrial metabolism was mimicked by a truncated Mfn2 mutant that is inactive as a mitochondrial fusion protein. Our results indicate that Mfn2 triggers mitochondrial energization, at least in part, by regulating OXPHOS expression through signals that are independent of its role as a mitochondrial fusion protein.


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